Recently we and others have demonstrated that bone marrow transplantation (BMT) into the APP{swe}/PS1AE9 double transgenic mouse model of Alzheimer's disease (AD) leads to a ~50% reduction in cerebral cortical and hippocampal B-amyloid (AB), both soluble and in plaques. We hypothesize that nonmyeloablative or mini BMT will be a safe and effective therapy for the treatment of AD, and hypothesize that its efficacy can be enhanced by genetic manipulation of the donor cells. To that end, the Specific Aims in this application focus on effects of BMT and reduced AB on measures of neurotoxicity, on mechanisms of AB reduction, and on approaches to reduce preconditioning toxicity and to enhance transplant efficacy. In Specific Aim 1, we test the hypothesis that BMT-mediated AB reduction is due to an immune response of self to non-self by transplanting cells from APP{swe}/PSI AE9 or wt mice, with or without GFP, into APP{swe}/PS1AE9 mice. The results will provide critical information relevant not only to mechanisms of AB reduction but that may guide the clinical application of this technology (allogeneic vs. autologous grafts). In Specific Aim 2, we test the hypothesis that genetic manipulation of donor cells can be performed to enhance efficacy of the therapy, by transplanting BM from mice that lack prostaglandin receptor EP2, which is integral to control of microglial phagocytosis and paracrine neurotoxicity. In our preliminary data we have shown that BMT with donor EP2-/-mice leads to a further significant reduction in cortical AB plaques, but we wish to expand on these experiments by examining soluble AB and associated neurotoxicity. Results of these experiments may guide future work into genetic manipulation of allogeneic or even autologous BM to customize treatments based on disease and host. Finally, since myeloablative preconditioning for BMT is associated with significant toxicity, in our third Specific Aim we test that hypothesis that BMT in mice with non-myeloablative preconditioning will also result in decreased AB, which will be critical in future clinical application in elderly patients. In each of the Specific Aims we correlate changes in AB with measures of neurotoxicity. The translational experiments proposed herein will lay the groundwork for possible future applications of BMT for AD and other neurodegenerative diseases.